Mesoscopic Aggregation of Folded Proteins

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To perform their function, proteins must operate in the crowded environment of a living cell, thus requiring mechanisms that prevent protein aggregation. When these mechanisms fail, pathological conditions, such as sickle cell anemia or plaque formation, take place. In some cases, on the other hand, specific types of aggregation are actually desirable; examples including storage of insulin in the pancreas and protein in grains, in the form of crystals. Making protein crystals remains the single most important tool for protein structure determination, which is crucial for understanding protein function. It comes as a surprise that for those protein aggregates to form, folded protein molecules must first organize into long-lived clusters of a protein-rich liquid that are about a micron in size: According to the existing paradigms of phase equilibrium, such mesoscopic clusters should not exist, nor have they been seen in other similar systems such as colloids. The project aims to elucidate the molecular mechanism and the thermodynamic basis of how the puzzling mesoscopic clusters form. To accomplish this goal, the project will combine the theoretical and experimental efforts of the Lubchenko and Vekilov labs using four proteins as model systems: lysozyme, hemoglobin, insulin, and lumazine synthase. The roles of water structuring at the protein-solvent interface and the formation of transient protein oligomers in the stabilization of the protein-rich phase will be investigated by molecular modeling and tested by means of dynamic/static light scattering and thermodynamic and rheological characterizations. The rich kinetics of the formation/decay of clusters resulting from the interplay between protein transport and oligomer formation will be worked out by solving non-linear kinetic schemes coupled with diffusion/advection and tested against measured life-times and sizes of the clusters. The solution of the important problem of mesoscopic aggregates in concentrated protein solutions lies at the interface of biology, physics, chemistry, and materials science. In addition, this research will be a close collaboration between a theoretical and experimental group from departments of chemistry and chemical engineering. These factors will combine to create a unique multidisciplinary research environment for participating students and research infrastructure. Considering the ethnic diversity at the University of Houston and in the greater Houston area, the research will enhance the educational opportunities in several underrepresented groups and promote their participation in advanced research. Existing collaborations with local writers and radio personalities will be utilized to publicize the societal benefits of the research. In addition to the fundamental and clinical significance of the research, its benefits include new potential routs for manufacturing novel materials and improving the nutritional value of crops. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and by the Physics of Living Systems program in the Physics Division.